The invention is concerned with processes for the manufacture of a pyrrolidine-3,4-dicarboxamide derivative of formula (X)
namely (3R,4R)-1-(2,2-difluoroethyl)-pyrrolidine-3,4-dicarboxylic acid 3-[(5-chloro-pyridin-2-yl)-amide]-4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Further, the invention is concerned with intermediates useful for those processes.
The compound of formula (X), which is disclosed in WO2005/092881, is an active compound and inhibits the coagulation factor Xa. This compound consequently influences blood coagulation, and therefore inhibits the formation of thrombin and can be used for the treatment and/or prevention of thrombotic disorders, such as amongst others, arterial and venous thrombosis, deep vein thrombosis, peripheral arterial occlusive disease (PAOD), unstable angina pectoris, myocardial infarction, coronary artery disease, pulmonary embolism, stroke (cerebral thrombosis) due to atrial fibrillation, inflammation and arteriosclerosis. This compound has potential benefit in the treatment of acute vessel closure associated with thrombolytic therapy and restenosis, e.g. after transluminal coronary angioplasty (PTCA) or bypass grafting of the coronary or peripheral arteries and in the maintenance of vascular access patency in long term hemodialysis patients. The compound of formula (X) may form part of a combination therapy with an anticoagulant with a different mode of action or with a platelet aggregation inhibitor or with a thrombolytic agent. Furthermore, the compound of formula (X) has an effect on tumor cells and prevents metastases. This compound can therefore also be used as antitumour an agent.
WO2005/092881 discloses a process for preparing the compound of formula (X). However, the process described in WO2005/092881 (in the examples) led to a low overall yield for the preparation of compound of formula (X). Also, some issues like the multiple solid additions of a paraformaldehyde/N-Bn-glycine mixture to a hot solution of diethyl fumarate for the [3+2] cycloaddition reaction, the low and varying yields of the Weinreb amidation step using the pyrophoric trimethyl aluminium, the use of large excess of alkylating agent (difluoroethyl triflate) and the moderate yield in the last step as well as the potentially unsafe combination of K2CO3 and DMSO at high temperature (for the N-arylation step) are not suitable for the up-scaling of the process.
Thus, the present invention provides improved methods for the manufacture of the compound of formula (X).